Introduction Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder characterised by partial oculocutaneous albinism, a bleeding diathesis, immunological dysfunction and neurological impairment. Bi-allelic loss-of-function variants in LYST cause CHS. LYST encodes the lysosomal trafficking regulator, a highly conserved 429 kDa cytoplasmic protein with an unknown function.
Methods To further our understanding of the pathogenesis of CHS, we conducted clinical evaluations on individuals with CHS enrolled in our natural history study. Using genomic DNA Sanger sequencing, we identified novel pathogenic LYST variants. Additionally, we performed an extensive literature review to curate reported LYST variants and classified these novel and reported variants according to the American College of Medical Genetics/Association for Molecular Pathology variant interpretation guidelines.
Results Our investigation unveiled 11 novel pathogenic LYST variants in eight patients with a clinical diagnosis of CHS, substantiated by the presence of pathognomonic giant intracellular granules. From these novel variants, together with a comprehensive review of the literature, we compiled a total of 147 variants in LYST, including 61 frameshift variants (41%), 44 nonsense variants (30%), 23 missense variants (16%), 13 splice site variants or small genomic deletions for which the coding effect is unknown (9%), 5 in-frame variants (3%) and 1 start-loss variant (1%). Notably, a genotype–phenotype correlation emerged, whereby individuals harbouring at least one missense or in-frame variant generally resulted in milder disease, while those with two nonsense or frameshift variants generally had more severe disease.
Conclusion The identification of novel pathogenic LYST variants and improvements in variant classification will provide earlier diagnoses and improved care to individuals with CHS.
- neurodegenerative diseases
- molecular medicine
- human genetics
Data availability statement
All data relevant to the study are included in the article or uploaded as supplemental information.
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Contributors MM, E-RN, CK and JCR acquired, analysed and interpreted genetic data (MM performed literature review and ACMG classification of variants; E-RN, CK and JCR performed cell culture and DNA extraction; CK and JCR performed Sanger sequencing; DRA validated the variants under
CLIA (Clinical Laboratory Improved Ammendments) -approved protocols and MCVM interpreted genetic data). JIG, SMH, SDR, JB, WAG and WJI clinically evaluated patients and interpreted clinical data. CC organised the patient samples and E-RN and MH organised the clinical data. MM, E-RN, JS-V, PS, WJI and MCVM drafted the manuscript. MM, JCR, DRA, JIG, MH, CT, WAG, WJI and MCVM critically revised the manuscript. WAG, WJI and MCVM conceptualised and supervised the study. All authors reviewed the manuscript. MCVM acts as the guarantor and accepts the full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.
Funding This study was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (Bethesda, Maryland, USA).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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